The present invention is concerned with a new group of metal complexes, particularly Pt complexes, which demonstrate antitumor activity. The complexes also possess radiosensitizing activity whereby cells or tissues can be made more sensitive to the killing effects of ionizing radiation when the complexes of the invention are used before, during, or after irradiation.
Broadly speaking, the complexes of the invention are (+)-charged dye complexes obtained by reacting a (+)-charged dye with a metal compound, preferably a platinum compound or compound of another platinum group metal, and more preferably a Pt(II) compound. A particularly preferred complex according to the invention is the product obtained by reacting a platinum(II) compound with rhodamine-123, hereinafter referred to as Pt(Rh-123). However, generally similar complexes prepared by using other charged dyes, as described below, are also contemplated.
The complexes of the invention may be made by reacting an organic or inorganic platinum compound or the equivalent with rhodamine 123 or other (+)-charged rhodamine or the like, for example, a cyanine dye such as:
3,3'-diethylthiadicarbocyanine iodide PA0 3,3'-diethyloxatricarbocyanine iodide (027) PA0 3,3'-diethyloxadicarbocyanine iodide PA0 3,3'-diethylthiatricarbocyanine iodide stains all (SA), or other (+)-charged cyanine dyes, PA0 tetraarylphosphonium salts bearing amino, hydroxyl or mercapto substituents, PA0 decaqualinium chloride (Deca) or other (+)-charged organic compounds.
Typically suitable platinum compounds include potassium tetrachloroplatinate (II) or like alkali metal tetrahaloplatinate (II); or cis-bis(acetonitrile)dichloroplatinum (II).
The reaction between the platinum compound and the rhodamine 123, or equivalents thereof, may be represented as follows, using potassium tetrachloroplatinate and rhodamine 123 for purposes of illustration: EQU K.sub.2 PtCl.sub.4 +2Rh-123.fwdarw.PtCl.sub.2 (Rh-123).sub.2 +2KCl
The reaction is conveniently carried out by adding an organic or aqueous solution of the rhodamine 123 or equivalent to an organic or aqueous solution of the platinum compound, preferably while stirring, and allowing the reaction mixture to stand at room temperature (20.degree.-25.degree. C.) until the desired complex precipitates out. The precipitate may be separated and washed in conventional fashion to provide the product in an essentially pure state. Heat may be applied in some instances to facilitate the desired complexing reaction but usually it is adequate to employ temperatures in of 20.degree.-25.degree. C. The reaction is usually completed in 10-24 hours.
In some cases the molar ratio of dye to platinum compound is 2:1; in other cases equimolar amounts of the reactants may be used although this is not critical. In any case, not more than 25% molar excess of either reactant is usually employed.
The present complexes demonstrate antitumor activity as shown on standard tests using MB 49 bladder carcinoma, P388 and L1210 leukemias and Lewis lung carcinoma. Based on the degree of activity demonstrated in the experimental tumors, the present complexes should be useful for their antitumor activity in essentially the same way, including dosages and mode of administration, as known antitumor Pt-complexes, e.g. cisplatin.
The invention is illustrated, but not limited, by the following: